Penetration of Cerebral Spinal Fluid into the Brain Parenchyma Using Temporally Patterned Neuromodulation

ABSTRACT

Electrical stimulation of specific facial and lingual nerves creates a more sustained pulsatility activity compared to stimulation of other cranial nerves. Pulsatility of arteries has intrinsic time constraints related to the time for vasodilation/constriction and time to return to baseline (TBL) after electrical stimulation which may affect the pulsatility response. Control of temporal patterning and the stimulation waveform maximizes the physiological response to cerebral pulsatility and its resulting effects on cerebral spinal fluid penetration into the brain parenchyma for a multitude of therapeutic uses including clearing misfolded proteins and/or administered pharmacological agents, diluting endogenous neurochemical concentrations within the brain, and reducing non-synaptic coupling.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/935,386, filed Jul. 22, 2020, which claims the benefit of U.S.Provisional Application No. 62/884,002, filed Aug. 7, 2019, both ofwhich are hereby incorporated by reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under N66001-17-2-4010awarded by the DOD/DARPA. The government has certain rights in theinvention.

BACKGROUND OF THE INVENTION

The present invention relates to electrical stimulation of target nervesto enhance waste clearance in the brain.

The central nervous system (CNS) lymphatic system is made up of multiplecomponents and pathways including the glymphatic system. The glymphaticsystem (or glymphatic clearance pathway) is a macroscopic wasteclearance system for the vertebrate CNS utilizing a unique system ofperivascular tunnels formed by glial cells to promote efficientelimination of soluble and insoluble proteins and metabolites from theCNS. The pathway provides a para-arterial influx route for cerebralspinal fluid (CSF) to travel in the perivascular space surroundingdescending vasculature and enter the brain parenchyma through AQP4channels, and a clearance mechanism via convective movement ofinterstitial fluid (ISF) for extracellular solutes such as misfoldedproteins and unwanted metabolites to be removed from the brain.

The aggregation of pathogenic proteins β-amyloid, α-synuclein, and C-tauin the brain may cause the deleterious effects of numerous diseases anddisorders such as traumatic brain injury/chronic traumaticencephalopathy, epilepsy, Alzheimer's disease, and Parkinson's disease.Removal of these pathogenic proteins has been found to have substantialtherapeutic benefit, for example, in treating traumatic braininjury/chronic traumatic encephalopathy, epilepsy, Alzheimer's disease,and Parkinson's disease.

Increasing the penetration of CSF into the brain parenchyma can servemany therapeutic purposes, including diluting endogenous neurochemicaltransmitter concentrations within the brain, altering the clearancerates of drugs delivered orally that penetrate through the blood-brainbarrier or delivered via a catheter system to the brain, and reducingnon-synaptic coupling between neurons to treat diverse conditionsleading to increased neural activity including anxiety disorders,tremor, and seizure.

Transport of CSF along the periarterial spaces into the brain parenchymaand into the cervical and thoracic lymph nodes is driven by cerebralarterial pulsation to the brain. It has previously been found thatligation of the carotid artery or administration of a centralsympatholytic such as dobutamine can alter the pulsatility of thecerebral vasculature to drive CSF movement in the associatedperivascular space.

SUMMARY OF THE INVENTION

The present inventors have found that electrical stimulation of easilyaccessible neural inputs located outside of the brain and amenable tominimally invasive or non-invasive stimulation strategies can inducecardiovascular and respiratory changes, dilate arterial vessels andincrease the pulsatility (change in the vessel diameters over timerelative to a mean vessel diameter) of penetrating arterial vessels inthe brain thus leading to increased clearance of misfolded proteins fromthe brain. Specifically, electrical stimulation of cranial nerves orlocal areas around the cranial nerves may selectively cause oscillationsin pressure and dilation of arteries that help to improve wasteclearance in the brain. However, these methods are limited by the body'scompensation responses that quickly habituate these effects over timeand do not maintain a sustained response when nerves are continuouslyand repeatedly electrically stimulated. In this respect, continuousstimulation of the cranial nerves only causes brief transient changes inblood flow.

The present inventors recognize that pulsatility of arteries hasintrinsic time constraints related to the time forvasodilation/constriction and time to return to baseline (TBL) afterelectrical stimulation, which may affect the pulsatility response. Inthis respect, these time constraints for stimulation inducedvasodilation/constriction and subsequent return to baseline define themaximum and minimum changes to pulsatility. The present inventionprovides control of temporal patterning and the stimulation waveform inorder to maximize the physiological response to cerebral pulsatility andits resulting effects on brain waste clearance. Thus, the electricalstimulation is temporally patterned to generate multiplevasodilation/constriction pulses in succession to optimize and sustainthe pulsating action to continuously drive CSF into the brain parenchymaover long periods of time.

Electrical stimulation of specific cranial nerves such as the branchesof the trigeminal nerve, i.e., buccal and lingual branch nerves, and thefacial nerve creates a more sustained pulsatility activity compared tostimulation of other cranial nerves. One possible explanation for thisis that the facial and trigeminal nerves have directsympathetic/parasympathetic innervation of the cerebral vasculaturethrough several routes, including through the sphenopalatine ganglion(SPG), which are part of neural pathways that directly control thevasodilation/constriction of the cerebral arteries. As a result, thetime course for dilation and constriction after a stimulation burst canbe quicker than other cranial nerves because the response is quickerthan inputs from the spinal cord which change peripheral sympathetictone or peripheral inputs such as the sciatic nerve that change bloodflow primarily through sensory activity mediated neurovascular coupling.

Also, stimulation through pathways that changesympathetic/parasympathetic tone outside the brain dilate the peripheralvasculature outside of the brain. The change in blood flow in the brainis primarily in response to this change in peripheral blood flow tomaintain perfusion (there are also occasionally indirect connectionsbetween the vagus and facial nerve in some subjects). As vagus nervestimulation only indirectly influences blood flow in cerebralvasculature, it has a slower time constant between burst of stimulationfor changes in flow to return to normal.

Therefore, the present invention provides 1) a unique intraoral deviceto conveniently and non-invasively activate the facial/trigeminal nervesand 2) unique temporal stimulation patterns to increase CSF flow via thetrigeminal/facial nerves, nerve inputs associated with the baroreflex(vagus, aortic depressor, carotid sinus, baroreceptor beds in the bulb,aorta), and peripheral nerve inputs not clearly associated with thebaroreflex (median nerve, sciatic nerve, tibial nerve, spinal cord).

1) A Unique Intraoral Device to Conveniently and Non-Invasively Activatethe Facial/Trigeminal Nerves

Specifically, the present invention provides an electrical stimulationdevice for improving waste clearance through the perivascular system ofthe blood brain barrier including at least one electrode configured tostimulate a facial nerve; an electrical generator generating a carrierwave having a carrier frequency stimulating the perivascular system intoincreased CSF/ISF flow; a modulator receiving the carrier wave and amodulation wave to modulate the carrier wave for application to at leastone electrode; and an electrical modulation generator generating themodulation wave having a predetermined periodicity providing a firstperiod of stimulation of the perivascular system and a second period ofrelaxation of the perivascular system, the predetermined periodicityselected to increase pulsatility over continuous stimulation of theperivascular system by the carrier frequency.

It is thus a feature of at least one embodiment of the present inventionto utilize increased cerebral blood flow through arterial vessels toimprove the penetration of cerebrospinal fluid into the brainparenchyma.

The electrode may include a cathode positioned distally with respect toa lingual or facial nerve ending and an anode positioned proximally withrespect to the lingual or facial nerve ending. The cathode and the anodemay be spaced apart along an axis substantially parallel to the nerve.The cathode and anode may be reversed depending on local anatomy.

It is thus a feature of at least one embodiment of the present inventionto generate a circuit of electrical impulses along the nerve fibers.

At least one electrode may be adapted to stimulate at least one of atrigeminal nerve, buccal branch nerve, mental branch nerve and facialnerve.

It is thus a feature of at least one embodiment of the present inventionto create stimulus locked changes in cerebral blood flow as compared tostimulation of nerves where habituation occurs.

The at least one electrode may be supported by a mouthpiece engaging ajaw of a user's mouth.

It is thus a feature of at least one embodiment of the present inventionto utilize the anatomical consistency of the nerves in the jaw regionwith respect to the jawbone to easily approximate nerve stimulationlocations, for example, through the mental foramen.

The mouthpiece may be comprised of a curved tube having an inner andouter wall flanking a channel receiving an upper or lower dental arch ofa user and covering an outer labia gingiva of the teeth. At least oneelectrode may be supported by an inner surface of the outer wall tocontact the labia gingiva.

It is thus a feature of at least one embodiment of the present inventionto utilize the hydrated epithelial tissue below the gingiva mucosa toprovide a conductive path for more efficient electrical stimulation ofnerves.

A cathode electrode may be positioned toward a front of the curvedmouthpiece receiving the anterior teeth and an anode electrode ispositioned toward a rear of the mouthpiece receiving the premolar teeth.The cathode electrode may be positioned to overlay nerve endings of themental branch nerve with less than 1 cm distance between the cathodeelectrode and the nerve endings.

It is thus a feature of at least one embodiment of the present inventionto provide precise electrical access to the nerve endings where thenerves are positioned close to the outer epidermis of the epithelialtissue.

The mouthpiece may support a first anode-cathode electrode pair on aleft side of the mouthpiece and a second anode-cathode electrode pair ona right side of the mouthpiece.

It is thus a feature of at least one embodiment of the present inventionto carry multiple electrode pairs for simultaneous multi-nervestimulation.

The at least one electrode may be supported by a dental filling insertedwithin a cavity of the tooth. The at least one electrode may besupported by a dental implant inserted within a jawbone.

It is thus a feature of at least one embodiment of the present inventionto utilize precise electrical access to the nerve endings of the molarteeth in close proximity to the roots of the molar teeth.

Sensors detecting salivary biomarkers may indicate a change to CSF flowselected from at least one of the following: amyloid beta peptide, tauprotein, lactoferrin, alpha-synuclein, DJ-1 protein, chromogranin A,huntingtin protein, DNA methylation disruptions, and micro-RNA.

It is thus a feature of at least one embodiment of the present inventionto provide quick visual indication of improved waste clearance throughknown biomarkers in the patient's saliva.

Electrodes may be used to record electrophysiological signals to detectchanges in low frequency power brain waves that propagate outside thecalvarium. Electrodes may also be used to pick up heart rate and heartrate variability.

It is thus a feature of at least one embodiment of the present inventionto provide quick visual indication of engagement of the stimulatingelectrodes with the nerves.

2) Unique Temporal Stimulation Patterns to Increase CSF Flow Via theTrigeminal/Facial Nerves, Nerve Inputs Associated with the Baroreflex(Vagus, Aortic Depressor, Carotid Sinus, Baroreceptor Beds in the Bulb,Aorta), and Peripheral Nerve Inputs not Clearly Associated with theBaroreflex (Median Nerve, Sciatic Nerve, Tibial Nerve, Spinal Cord)

An alternative embodiment of the present invention may provide a methodof improving waste clearance through the perivascular system of theblood brain barrier including positioning at least one electrode inclose proximity to a nerve; generating a carrier wave having a carrierfrequency stimulating the perivascular system into increased CSF/ISFflow; generating the modulation wave having a predetermined periodicityproviding a first period of stimulation of the perivascular system and asecond period of relaxation of the perivascular system, thepredetermined periodicity selected to increase pulsatility overcontinuous stimulation of the perivascular system by the carrierfrequency; and modulating the carrier wave and applying the carrier waveto the electrode.

For stimulation of the facial nerves, trigeminal nerves, andsphenopalatine ganglia the carrier frequency of the carrier wave may bebetween 25 Hz and 55 Hz and centered around 50 Hz. The modulation wavemay have a frequency between 0.5 Hz and 0.1 Hz. The modulation wave mayhave a time duration (“bursts”) of between 1 second and 10 seconds witha pulse interval (unstimulated period between “bursts”) between 1 secondand 10 seconds.

For stimulation of the vagus nerve, carotid sinus nerve, andbaroreceptors the carrier frequency of the carrier wave may be between20 Hz and 50 Hz and centered around 30 Hz. The modulation wave may havea frequency between 1/45 Hz and 1/180 Hz. The modulation wave may have atime duration (“bursts”) of between 15 second and 60 seconds and around30 seconds with a pulse interval (unstimulated period between “bursts”)between 30 seconds and 120 seconds and around 60 seconds.

For stimulation of the sciatic nerve and peripheral nerve the carrierfrequency of the carrier wave may be between 20 Hz and 55 Hz andcentered around 50 Hz. The modulation wave may have a frequency between1/300 Hz and 1/540 Hz. The modulation wave may have a time duration(“bursts”) of between 1 minute and 4 minutes and around 3 minutes with apulse interval (unstimulated period between “bursts”) between 4 minutesand 6 minutes and around 5 minutes.

It is thus a feature of at least one embodiment of the present inventionto introduce periods of relaxation into the electrical stimulationparameters to improve recovery processes of the dilated blood vessels.

At least one electrode may be positioned over the mental branch nerve.At least one electrode may be positioned over the inferior alveolarnerve.

These particular objects and advantages may apply to only someembodiments falling within the claims and thus do not define the scopeof the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram of a human skull receiving electricalstimulation from electrodes positioned on facial and lingual nerves ofthe head in the tooth and jaw region in accordance with the presentinvention;

FIG. 2 is a block diagram showing an electrical stimulator modulating acarrier wave to produce a modified electrical signal providing increasedCSF flow through arterial vessels to the head and therefore increasingwaste clearance;

FIG. 3 is a graph showing a magnitude of vasodilation/constriction ofarterial vessels relative to a mean vessel diameter as a function of atime to return to baseline (TBL) at a given electrical stimulationfrequency and duty cycle;

FIG. 4 is a top plan view of a mouthpiece placed in a user's mouth andover the lower jaw to deliver directed electrical stimulation to mentalbranch nerves within the oral mucosa;

FIG. 5 is a perspective cutaway view of FIG. 5 showing the mouthpieceplaced within the user's mouth and electrodes of the mouthpiececontacting the oral mucosa to stimulate the mental branch nerves;

FIG. 6 is a sectional view of a dental filling and dental implant placedwithin a user's jaw to deliver directed electrical stimulation to, forexample, an inferior alveolar nerve of the second and third molars;

FIG. 7 is a schematic diagram of a human head receiving electrodes on orin a cheek region to deliver directed electrical stimulation to a buccalbranch of the lingual nerve within the cheek region;

FIG. 8 is a graph, similar to FIG. 3, showing a magnitude ofvasodilation/constriction of arterial vessels relative to a mean vesseldiameter as a function of a time to return to baseline (TBL) at anoptimal electrical stimulation frequency and duty cycle for stimulationof the facial nerves, trigeminal nerves, and sphenopalatine ganglia;

FIG. 9 is a graph, similar to FIG. 3, showing a magnitude ofvasodilation/constriction of arterial vessels relative to a mean vesseldiameter as a function of a time to return to baseline (TBL) at anoptimal electrical stimulation frequency and duty cycle stimulation ofthe vagus nerve, carotid sinus nerve, and baroreceptors; and

FIG. 10 is a graph, similar to FIG. 3, showing a magnitude ofvasodilation/constriction of arterial vessels relative to a mean vesseldiameter as a function of a time to return to baseline (TBL) at anoptimal electrical stimulation frequency and duty cycle for stimulationof the sciatic nerve and peripheral nerve.

DETAILED DESCRIPTION OF THE INVENTION Background—Facial/TrigeminalNerves

Referring now to FIG. 1, a typical human skull 10 supports a number ofcranial nerves 12 emerging directly from the brain, located within theskull 10, and emerging out through cranial foramina 14, or holes, in theskull 10 to reach their final destinations on the exterior of the skull10 and around the jaw and neck region. These cranial nerves 12 relayinformation between the brain and other parts of the body.

The trigeminal nerve 20 (fifth cranial nerve) is the largest of thecranial nerves 12 and provides sensation to the face and various motorfunctions such as biting and chewing functions. The trigeminal nerve 20includes three major branches: the ophthalmic nerve (V1) 22, themaxillary nerve (V2) 24, and the mandibular nerve (V3) 26. Themandibular nerve (V3) 26 includes several sub-branches including thelingual nerve 28 and the inferior alveolar nerve 30 that have shown tobe particularly receptive to electrical stimulation. The facial nerve(seventh nerve) has also been shown to be receptive to electricalstimulation.

The mental branch nerves 40 are a sub-branch of the inferior alveolarnerve 30 and provide sensation to the front of the chin, lower lip,labial gingiva of the mandibular anterior teeth and the premolars. Thebuccal branch nerves 42 are a sub-branch of the lingual nerve 28 thatprovides sensation to the cheek and the second and third molar teeth.The locations of the mental branch nerves 40 and buccal branch nerves 42in and around the jawbone 44 place the stimulation points or respectivenerve endings 46 close to the outermost epidermis of the skin making itan ideal location for electrical stimulation where the distance andimpedance between an electrode 50 and the target nerve may be minimized.In this respect lower amounts of electrical energy may be needed tostimulate these sensory nerves compared to nerves located deeper withinthe skin and which may require more invasive procedures to stimulate thenerves.

Electrodes 50 placed at or proximate to the mental branch nerves 40 andbuccal branch nerves 42 allow for electrical stimulation of therespective nerves to therefore elicit a sustained response of thearterial vessels to dilate/constrict in a pulsating manner, as furtherdiscussed below. In one embodiment of the present invention, theelectrodes 50 are positioned over the mental foramen which may transmitelectrical stimulation to the terminal branches of the inferior alveolarnerve and vessels of the mental artery

In one embodiment of the present invention, as further discussed belowwith respect to FIGS. 4 through 6, the electrodes 50 may be a part of anintraoral device 52 placed in the mouth, such as a mouthguard, dentalfilling or dental implant, to electrically stimulate the inferioralveolar nerve 30 and mental branch nerves 40 located near or around thelower jawbone 44 region. In an alternative embodiment of the presentinvention, as further discussed below with respect to FIG. 7, theelectrodes 50 may be surface electrodes placed on an outer surface ofthe cheek, or subcutaneous electrodes inserted under the skin in thecheek region to electrically stimulate the buccal branch nerves 42located in the upper jawbone 44 region and the facial nerves below thecheek.

Temporal Stimulation Patterns to Increase CSF Flow

Referring now to FIG. 2, an optimization of the temporal patterning andstimulation parameters may maximize the cerebral pulsatility andincrease the CSF flow to maximize waste clearance from the brain. Thepulsatility may be defined as a change in the vessel diameter over timerelative to a mean vessel diameter.

Electrical stimulation of the target nerves may be accomplished using anelectrical stimulator 58 such as those commercially available fromTucker-Davis Technologies of Alachua, Fla. or A-M Systems of Sequim,Wash. The electrical stimulator 58 may include a carrier wave generator60 having a processor 102 being an electronic computer having aself-contained nonvolatile memory 103 holding an operating program 105and necessary storage variables as will be described below. Thenonvolatile memory 103 may comprise, for example, flash memory and/orread only memory, or other similar nonvolatile memory as contextrequires, which may store data values to be retained even in the absenceof electrical power. The processor 102 may be a STM32 Nulceo board orPIC microcontroller as known in the art.

The processor 102 provides various inputs and output linescommunicating, for example, with one or more stored programs 105 storedin non-transitory memory 103 and the carrier wave generator 60 togenerate a carrier wave 62 at a carrier frequency and amplitude. In oneembodiment, the processor 102 may be external to the intraoral device 52and communicate wirelessly with the carrier wave generator 60 on theintraoral device 52. In an alternative embodiment, the processor 102 maybe mounted on a flexible printed circuit board and incorporated ormolded onto the intraoral device 52 to communicate with the carrier wavegenerator 60 on the intraoral device 52 via a wired connection.

The carrier wave 62 is delivered to a modulator 64 modulating thecarrier wave 62 amplitude according to a modulating signal 70. In asimplest configuration, modulator 64 passes the carrier wave 62 withoutmodification during a first stimulation period 66 and/or turns off thecarrier wave 62 during a second period 68. In this case, the modulatingsignal 70 may be a discontinuous waveform such as a pulse or squarewave. As is understood in the art, signal modulation by the modulator 64may provide an envelope of the peaks of the carrier wave 62, the latterbeing of much higher frequency than the modulating signal 70. Althoughthe modulating signal 70 is shown as a square wave in FIG. 2, themodulating signal 70 may also be a smooth curve as shown in FIG. 3.Referring also to FIG. 3, the stimulation parameters of the modulatingsignal 70 may be empirically set in order to maximize CSF flow througharterial vessels to the brain. This set point may be established, forexample, by monitoring a set of patients being scanned in a computedtomography (CT) scanner or magnetic resonance imaging (MRI) scanner withcontrast media to detect CSF/ISF flow and adjusting the stimulation timeand relaxation time to maximize the area 80 beneath the CSF/ISF flowcurve 82. These settings may then be used generally for all patients ormay be optimized for particular patient classes such as by age, heightand weight, and sex. Ideally the set point will provide a relaxationtime (pulse interval 68) that is no less than the time to return tobaseline (TBL) measured after brief periods of stimulation (pulseduration 66). While the inventors do not wish to be bound by aparticular theory, it is believed that the accommodation or acclamationof the tissue to the stimulation effectively limits the clearance whencontinuous stimulation is provided as understood in the prior art. Byinterleaving stimulation (pulse duration 66) with periods of rest (pulseinterval 68), recovery processes of the glymphatic and meningeallymphatic system may be accommodated to allow greater clearance longrun.

Thus, the dilation/constriction of arterial vessels at variousmodulating signal frequencies may be compared to maximize the area 80under the curve 82 of FIG. 3, for example, slow, large amplitude changesin clearance (produced by prolonged carrier frequency stimulation) maybe compared with faster, smaller amplitude changes in clearance(produced by shortened carrier frequency stimulation) to provide thegreatest increases in CSF flow over time in the perivascular space.Similar comparisons may be done with respect to the spacing betweenstimulation provided by the relaxation period.

The following are exemplary embodiments of modulating signal frequenciesfor specific target nerves optimized to create a full pulse withoutattenuating the peak flow response but accelerating the return tobaseline.

Example 1: Facial Nerves, Trigeminal Nerves, and Sphenopalatine Ganglia

Referring to FIG. 8, the carrier wave 62 may be a single frequencywaveform (e.g. a sine wave) with the frequency of the carrier wave 62less than 75 hertz, and between 20 hertz and 60 hertz and preferablybetween 25 hertz and 55 hertz, with the preferred range centered around50 hertz. At higher frequencies (75 Hz or above), habituation occursbefore peak flow change is obtained, causing a weaker effective pulse.

In some embodiments, the modulating signal 70 of the modulator 64 may bea single frequency, monophasic signal such as a sine wave creating“bursts” of electrical stimulation. The frequency of the modulatingsignal 70 is preferably between 0.5 hertz and 0.1 hertz. The modulatingsignal 70 may provide electrical stimulation 72 with electrical pulses74 having a time duration 66 between 1 second and 10 seconds, andpreferably 5 seconds, and pulse intervals 68 between 1 second and 10seconds, and preferably 5 seconds between pulses. Although the inventorsdo not wish to be bound by a particular theory, the introduction of arelaxation period where there is no stimulation (pulse interval 68)counterintuitively increases total clearance.

In one embodiment of the present invention, the carrier wave 62 may havea frequency between 5 kilohertz and 300 kilohertz for non-invasivestimulation. The carrier wave 62 may have a current amplitude of lessthan 100 microamps for invasive stimulation and less than 40 milliampsfor non-invasive stimulation and a voltage controlled to achieve thiscurrent per current control known in the art. The modulating signal 70may have a period between 15 microseconds and 5 milliseconds.

Although electrical stimulation has been shown and described withrespect to stimulating the facial nerves and trigeminal nerves, it isunderstood that the temporal patterning of the present invention mayalso be applied to other target nerves identified as providing increasedCSF flow, and as further described below with respect to Examples 2 and3.

Example 2: Vagus Nerve, Carotid Sinus Nerve, and Baroreceptor

Changes in cerebral vasculature blood flow driven by stimulation ofbaroreflex inputs such as the vagus nerve, aortic depressor nerve,carotid sinus nerve, and carotid sinus bulb/aortic arch are not drivenby direct connection to the cerebral vasculature. Instead, they dilatethe peripheral arteries through activation of the baroreflex pathway,and the cerebral vessels then react to maintain constant perfusion inthe brain. As this response is indirect it has a slower time constantfor temporal patterning. Stimulation must be maintained longer to causethis indirect effect on cerebral vasculature, and the habituation periodis driven by the entire system finding a new set point for homeostasis.The longer rest period is needed to allow the neural inputs indirectlygoverning the peripheral vasculature response to recover.

Referring to FIG. 9, the carrier wave 62 may be a single frequencywaveform (e.g. a sine wave) where the frequency of the carrier wave 62may be less than 75 hertz, and between 20 hertz and 75 hertz andpreferably between 25 hertz and 50 hertz, with the preferred rangecentered around 30 hertz. At higher frequencies (75 Hz or above), neuralhabituation occurs before peak flow change is obtained and/or unwantedchemoreceptor activation can occur, causing a weaker effective pulse.

In some embodiments, the modulating signal 70 of the modulator 64 may bea single frequency, monophasic signal such as a sine wave creating“bursts” of electrical stimulation. The frequency of the modulatingsignal 70 is preferably between 1/45 hertz and 1/180 hertz. Themodulating signal 70 may provide electrical stimulation 72 withelectrical pulses 74 having a time duration 66 between 15 seconds and 60seconds, and preferably 30 seconds, and pulse intervals 68 between 30seconds and 120 seconds between pulses, and preferably 60 seconds.Although the inventors do not wish to be bound by a particular theory,the introduction of a relaxation period where there is no stimulation(pulse interval 68) counterintuitively increases total clearance.

In one embodiment of the present invention, the carrier wave 62 may havea frequency between 5 kilohertz and 300 kilohertz for non-invasivestimulation. The carrier wave 62 may have a current amplitude of lessthan 100 microamps for invasive stimulation and less than 40 milliampsfor non-invasive stimulation and a voltage controlled to achieve thiscurrent per current control known in the art. The modulating signal 70may have a period between 15 microseconds and 5 milliseconds.

Example 3: Sciatic Nerve and Peripheral Nerve

The mechanism by which peripheral nerves influence blood flow in thecerebral vasculature blood flow that are not mediated by the baroreflexis by increasing activity in specific regions of the brain. Thisincrease in brain activity increases metabolic demand in these areas,and the vasculature of the brain compensates to increase supply, knownas neurovascular coupling. Consequently, the temporal patterning neededto optimize pulsatility of the cerebral vasculature is slower thandescribed for facial/trigeminal nerves that directly dilatecerevasculature or for baroreflex mediated response. This creates thesmallest increase in pulsatility of the neural input options described.However, as neural inputs such as the sciatic are superficial, they areoften easier to engage with non-invasive or minimally invasive surgicalstrategies. There is a delay for the blood flow to respond to theincreased metabolic demand, and the rest period is necessary to allowmetabolic demand/supply to return to normal before activating anotherpulse sequence.

Referring to FIG. 10, the carrier wave 62 may be a single frequencywaveform (e.g. a sine wave) with the frequency of the carrier wave 62may be less than 75 hertz, and between 20 hertz and 60 hertz andpreferably between 25 hertz and 55 hertz, with the preferred rangecentered around 50 hertz.

In some embodiments, the modulating signal 70 of the modulator 64 may bea single frequency, monophasic signal such as a sine wave creating“bursts” of electrical stimulation. The frequency of the modulatingsignal 70 is preferably between 1/300 hertz and 1/540 hertz. Themodulating signal 70 may provide electrical stimulation 72 withelectrical pulses 74 having a time duration 66 between 1 minute and 4minutes, and preferably 3 minutes, and pulse intervals 68 between 4minutes and 6 minutes between pulses, and preferably 5 minutes. Althoughthe inventors do not wish to be bound by a particular theory, theintroduction of a relaxation period where there is no stimulation (pulseinterval 68) counterintuitively increases total clearance.

The invention contemplates that at some point it may be possible toprovide real-time sensing of clearance. In that case the processor 102executing one or more stored programs 105 stored in non-transitorymemory 103 may automatically determine a frequency in which pulsatilityis maximized by providing variations in the above described parametersand monitoring clearance appropriately. Similarly, the processor 102 mayautomatically determine a minimum time duration of the electrical pulsesrequired to provide maximum effect.

In this respect, the real-time sensing of clearance, for example,monitoring preictal seizure activity or heart rate, may be used todetermine when additional electrical stimulation to the stimulationdevice is needed and further administered to the patient, or to alertthe patient or medical professional to deliver electrical stimulation tothe patient.

The CSF/ISF flow may be monitored using known imaging modalities such asCT scan, MRI scan, and panoramic x-ray during electrical stimulation. Itis understood that other physiological factors may also be monitored todetermine the effectiveness of stimulation parameters, such as changesto heart rate, respiratory rate, or presence of certain biomarkers inthe patient's blood or saliva as further described below. Thesephysiological factors may be measured using, for example, neuroimagingtechniques (e.g., panoramic x-ray, computerized topography (CT) scan,diffuse optical imaging (DOI), event-related optical signal (EROS),magnetic resonance imaging (MM), functional magnetic resonance imaging(fMRI), magnetoencephalography (MEG), positron emission tomography(PET), single-photon emission computed tomography (SPECT), and cranialultrasound), cognitive function testing (e.g., learning tests and memorytests), motor function testing, sensory function testing, biopsy, CSFtesting, blood testing and/or genetic testing.

Intraoral Device to Activate the Facial/Trigeminal Nerves

Referring to FIGS. 4 and 5, the electrical stimulation 72 of facial andlingual nerves may be facilitated by electrodes 50 placed on anintraoral device 52 placed within the mouth. The intraoral device 52 maybe used to conveniently and consistently position the electrodes 50 atspecific locations in the mouth to provide electrical stimulation 72 totarget nerves. For example, the electrodes 50 may be placed in closeproximity to the mental foramen and/or the inferior alveolar nerve 30and mental branch nerves 40, accessible through the labial gingiva 90and alveolar mucosa 92 of the mouth as described below. The hydratedepithelial tissue of the labial gingiva 90 and alveolar mucosa 92 assistto provide a conductive path to the target nerves.

In one embodiment of the present invention, the intraoral device 52 is amouthpiece 100 receivable into a patient's mouth and configured to carrythe electrical circuitry of the electrical stimulator 58 as describedabove with respect to FIG. 2, and generally including the processor 102and battery power supply 104 (for example, including rechargeable leadacid or lithium ion batteries) for delivery of electrical stimulation 72to the electrodes 50 within the mouth.

The mouthpiece 100 may be a mouthguard-type device made of a medicalgrade, non-conductive material such as acrylic, poly (vinylacetate-ethylene) copolymer clear thermoplastic, polyurethane, laminatedthermoplastic, or other medical grade plastic. The mouthpiece 100provides a cover that extends upward or downward over at least part ofthe teeth 106, labial gingiva 90, and optionally, alveolar mucosa 92 ina manner which would support electrodes 50 close to the labial gingiva90, and optionally, alveolar mucosa 92 overlaying the target nerves. Themouthpiece 100 may be custom molded to fit a specific patient's mouth,teeth 106 and jawbone 44. For example, the mouthpiece 100 may be 3Dprinted based on a CT scan of the jawbone 44. Alternatively, themouthpiece 100 may be manufactured at various predetermined sizes in amanner which would allow the mouthpiece 100 to fit different sizedmouths, teeth 106 and jawbones 44 of patients.

The mouthpiece 100 may be molded to receive both the upper and lowerdental arches of a patient's mouth when the jawbone 44 is closed and theteeth 106 bite down on the mouthpiece 100, similar to a conventionalsports mouthguard. However, it may be desired that the mouthpiece 100also be formed of separate upper and lower components which may be wornon one or both of the upper or lower dental arches of the patient'smouth, similar to a conventional dental retainer, so that the jawbone 44can be opened and closed when the mouthpiece 100 is worn.

In an exemplary embodiment showing a lower component mouthpiece 100, asillustrated in FIGS. 4 and 5, the mouthpiece 100 may be an arcuate tube107 having a circular or oval cross section cut along a generallylongitudinal plane to define a downwardly extending arch with adownwardly extending outer sidewall 108 and inner sidewall 110 extendinggenerally parallel and flanking outer and inner sides of the lower teeth106 respectively. A bottom of the arcuate tube 107 is open to reveal achannel 112 sized and shaped to receive the lower teeth 106 of thepatient's mouth. The arcuate tube 107 extends over a top of the lowerteeth 106 with the outer sidewall 108 extending downwardly along anouter side of the lower teeth 106 to partially cover at least part ofthe labial gingiva 90 and optionally the alveolar mucosa 92 on anoutside of the lower dental arch, while the inner sidewall 110 extendsdownwardly along a rear side of the lower teeth 16 and may at leastpartially cover the labial gingiva 90 and alveolar mucosa 92 on aninside of the lower dental arch. It is understood that the innersidewall 110 does not need to extend as far downwardly as the outersidewall 108 and is meant primarily to support the arcuate tube 107 overthe lower teeth 106.

The mouthpiece 100 may have an arcuate length extending rearwardly alonga curve generally correlating with the lower dental arch of the patient.The mouthpiece 100 may curve at a front end and extend rearwardly alongleft and rights sides of the lower jawbone 44 to cover the mandibularanterior teeth 106 a and the premolars 106 b. The mouthpiece 100 mayfurther extend rearwardly along left and rights sides of the lowerjawbone 44 to optionally further cover the second and third molar teeth106 c.

It is understood that an alternative embodiment of the mouthpiece 100that receives both the upper and lower dental arches of a patient'smouth when the jawbone 44 is closed and the teeth 106 bite down on themouthpiece 100 may similarly provide outer and inner sidewalls 108, 110flanking the lower teeth 106.

The outer and inner sidewalls 108, 110 of the mouthpiece 100 may supportthe electrical circuitry components of the electrical stimulator 58 suchas the processor 102 and the battery power supply 104. The processor 102and battery power supply 104 may be embedded within the sidewalls 108,110 of the mouthpiece 100 so that they do not interfere with the fit ofthe mouthpiece 100 over the lower dental arch. The processor 102 andbattery power supply 104 may communicate with the electrodes 50supported by the outer sidewall 108 to deliver the modulated electricalstimulation signal 72 to the electrodes 50 as described above.

The battery power supply 104 may provide power to the electricalstimulator 58 in a manner which allows for current delivery to theelectrodes 50. It is understood that an external power supply may alsobe used to deliver power to the electrical stimulator 58 in addition toor instead of the battery power supply 104. It is also understood thatthe electrical stimulator 58 may be positioned outside of the mouth andcommunicate remotely with a controller and electrodes 50 of themouthpiece 100.

A position of the electrodes 50 on the walls of the mouthpiece 100 maybe determined by a location of the mental branch nerves 40 and nerveendings 46 in the mouth. In this respect, medical imaging may be used tolocate the position of the mental branch nerves 40 in the mouth and toaid in placement of the electrodes 50 on the mouthpiece 100.Specifically, when the mouthpiece 100 is positioned in the patient'smouth, the electrodes 50 are desirably positioned on an interior side ofthe front sidewall 108 proximate the mandibular anterior teeth 106 a andthe premolars 106 b to abut or be placed in close proximity to thelabial gingiva 90 and alveolar mucosa 92 on the outside of the lowerdental arch in a manner which provides stimulation to the mental branchnerves 40.

The electrodes 50 may include a stimulating cathode electrode 50 aplaced close to the desired stimulation site, for example, near thenerve endings 46 of the mental branch nerves 40. An anode electrode 50 bmay then be placed proximal to the cathode electrode 50 a with respectto the nerve endings 46. In this respect, the electrical current flowsfrom the anode electrode 50 b to the cathode electrode 50 a so that thenerve endings 46 receives the stimulus and propagates an actionpotential upstream through the mental branch nerves 40. The cathodeelectrode 50 a and anode electrodes 50 b are spaced apart along an axisgenerally parallel to the course of the mental branch nerves 40.

Medical imaging may be used to facilitate precise placement of thecathode electrode 50 a close to the nerve ending and the preciseplacement of the anode electrode 50 b upstream from the cathodeelectrode 50 a and proximal to the nerve ending 46. The cathodeelectrode 50 a may be placed less than 2 cm or less than 1 cm from themental branch nerve ending 46 and the anode electrode 50 b may be placedless than 3 cm or less than 2 cm upstream from the cathode electrode 50a along the mental branch nerves 40.

It is understood that the pair of communicating electrodes, i.e., thecathode electrode 50 a and anode electrode 50 b, may stimulate at leastone of the left and right side mental branch nerves 40 of the mouth andthe mouthpiece 100 may include more than one pair of anode and cathodeelectrodes 50 a, 50 b to stimulate both the left and right mental branchnerves 40 of the left and right sides of the mouth. It is alsounderstood that more than two pairs of anode and cathode electrodes 50a, 50 b may be carried by the mouthpiece 100 to stimulate various areasalong the mental branch nerves 40. In some embodiments, changing thephase of the modulating signal 70 to different mental branch nerves 40may be used to enhance the stimulation of the mental branch nerves 40 bytiming the delivery of the electrical stimulation to the multiple pairsof electrodes. In one embodiment, electrical simulation may be rotatedacross several electrodes placed across the target nerve, to maximizeactivation of that nerve without activating nearby nerves responsiblefor unwanted side effects.

It is understood that an upper component mouthpiece may be described ina similar manner as the lower component mouthpiece described above andshown in FIGS. 4 and 5 whereby the upper component mouthpiece is rotated180-degrees about a horizontal axis to receive the upper dental archinstead of the lower dental arch and stimulate the superior alveolarnerves of the upper jawbone 44 in a similar manner, as would beunderstood by one having ordinary skill in the art.

Referring now to FIG. 6, in an alternative embodiment of the presentinvention, the intraoral device 52 may be a dental filling 120 insertedwithin a cavity or hole of the tooth 106, or a dental implant 122implanted within a hole of the gums and jawbone 44, to provideelectrical stimulation to the inferior alveolar nerve 30 located belowthe roots of the molar teeth 106.

In one embodiment, the intraoral device 52 may be dental filling 120inserted within a cavity or hole 123 drilled through a crown of a molartooth 106 (similar to a root canal procedure) to expose the pulp 124 ofthe tooth 106 normally carrying nerves and blood vessels from thehealthy tooth to nerves and blood vessels outside and below the tooth106. The dental filling 120 may include the electrical circuitry of theelectrical stimulator 58 described above with respect to FIG. 2 andstimulating electrodes 50. The electrodes 50 may include a cathodeelectrode 50 a and anode electrode 50 b separated within the dentalfilling 120 to provide electrical current flow therebetween and providecurrent flow into the pulp 124 of the tooth 106 thereby stimulating thenerves below the molar tooth 106 (second and third molar teeth 106 c)such as the inferior alveolar nerve 30.

In an alternative embodiment, the intraoral device 52 may be a dentalimplant 122 implanted within a hole 130 within the gums and jawbone 44caused by a removed or extracted tooth and providing an opening intowhich the dental implant 122 may be implanted. The dental implant 122may include the electrical circuitry of the electrical stimulator 58described above with respect to FIG. 2 and stimulating electrodes 50.The electrodes 50 may include a cathode electrode 50 a and anodeelectrode 50 b separated within the dental implant 122 to provideelectrical current flow therebetween and to provide current flow tonerves running below the hole 130 (below second and third molar teeth106 c) such as the inferior alveolar nerve 30. As understood in the art,the dental implant 122 may also include an implant crown 132 resemblinga real tooth worn over the top of the dental implant 122.

Referring to FIGS. 4 through 6, the intraoral devices 52 described abovemay include and support biomarker sensors 134 with fluorescentindicators indicating the presence of various analytes from tissue orsaliva indicating increased levels of neuronal cytokines indicative ofan increase in CSF flow to the brain. For example, amyloid beta peptide,tau protein, lactoferrin, alpha-synuclein, DJ-1 protein, chromogranin A,huntingtin protein, DNA methylation disruptions, and micro-RNA profilesmay be detected to show an increase in CSF.

The stimulating electrodes 50 or separate electrodes may be used torecord electrophysiological signals to detect changes in low frequencypower brain waves that propagate outside the calvarium. The electrodes50 may also be used to pick up heart rate and heart rate variability aswell.

Referring to FIG. 7, in another embodiment of the present invention,electrical stimulation of facial and lingual nerves may be facilitatedby electrodes 50 placed on or within the cheek region. The electrodes 50may be a surface electrodes or subcutaneous electrodes providingelectrical stimulation to the buccal branch nerves 26 located below theskin in the cheek region.

In one embodiment, the electrodes 50 are surface electrode pads placedexternally on the user's cheeks overlying the buccal branch nerves 26 tostimulate the buccal branch nerves 26 and/or facial nerves. Theelectrodes 50 may include a cathode electrode 50 a and anode electrode50 b placed externally on the same cheek. Current flow between the anodeand cathode electrodes 50 a, 50 b may provide electrical stimulation ofthe target nerve. A second set of anode and cathode electrodes 50 a, 50b may be placed on the opposite cheek to stimulate the buccal branchnerves 26 and/or facial nerves of the opposite cheek.

In an alternative embodiment, the electrodes 50 may be subcutaneouselectrodes inserted beneath the epidermis within the user's cheeks tostimulate the buccal branch nerves 26. The subcutaneous electrodes maybe injectable electrodes 50 such as liquid metal electrodes injectableusing a syringe 140 and withdrawable from the skin. The injectableelectrodes 50 may include a cathode electrode 50 a and anode electrode50 b placed under the skin. Current flow between the anode and cathodeelectrodes 50 a, 50 b may provide electrical stimulation of the targetnerve. The injectable electrodes 50 may be injected into one or both ofthe cheeks to stimulate the buccal branch nerves 26.

It is understood that the electrical stimulation describe above couldalso be accomplished with infrared activation, optogenetic activation,and transcranial/transdermal magnetic stimulation, and focusedultrasound.

The above described methods may be used to treat patients with forexample depression, anxiety and epilepsy by increasing the influx of CSFinto the brain parenchyma. It has been found that an increase in CSFinto the brain parenchyma further dilutes endogenous concentrations ofneurochemical transmitters/bioactive molecules and reduces ephaptic(non-synaptic) coupling implicated in abnormal circuit behaviorsassociated with multiple disorders of the nervous system, for example,anxiety disorders, epilepsy, Alzheimer's disease, and Parkinson'sdisease.

It is understood that the present invention is not limited to thetreatment of traumatic brain injury/chronic traumatic encephalopathy,epilepsy, Alzheimer's disease, and Parkinson's disease and the like andmay also be used to treat other conditions and disorders such ashydrocephalus caused by a buildup of CSF in the brain parenchyma byincreasing the clearance of CSF through the brain. Also, clearance oforally administered drugs that cross the blood brain barrier, ordrugs/biomolecules that are infused via an injection/catheter, can bemodulated by changing the CSF flow rate.

In addition to increasing pulsatility, electrical stimulation of thenerves as described above has been found to induce neuroplasticity orcortical plasticity and introduce and modify brain wave oscillationfrequency useful for treating neuro-psychiatric disorders. For example,brain wave oscillations may be increased to natural brain wavefrequencies, e.g., 8 to 13 hertz, which may be lower in older adultsexperiencing memory difficulties, and activation of circuitry throughthe trigeminal sensory nuclei to create broad neurochemical changes inthe brain mediated by cross connectivity to the nucleus of the solitarytract (NTS) to enhance plasticity in many conditions such as stroke andtinnitus. The NTS has inputs to locus coeruleus, raphae nucleus, andnucleus basalis which are responsible for most norepinephrine,serotonin, dopaminergic, and cholinergic projections to the rest of thebrain. Certain terminology is used herein for purposes of referenceonly, and thus is not intended to be limiting. For example, terms suchas “upper”, “lower”, “above”, and “below” refer to directions in thedrawings to which reference is made. Terms such as “front”, “back”,“rear”, “bottom” and “side”, describe the orientation of portions of thecomponent within a consistent but arbitrary frame of reference which ismade clear by reference to the text and the associated drawingsdescribing the component under discussion. Such terminology may includethe words specifically mentioned above, derivatives thereof, and wordsof similar import. Similarly, the terms “first”, “second” and other suchnumerical terms referring to structures do not imply a sequence or orderunless clearly indicated by the context.

When introducing elements or features of the present disclosure and theexemplary embodiments, the articles “a”, “an”, “the” and “said” areintended to mean that there are one or more of such elements orfeatures. The terms “comprising”, “including” and “having” are intendedto be inclusive and mean that there may be additional elements orfeatures other than those specifically noted. It is further to beunderstood that the method steps, processes, and operations describedherein are not to be construed as necessarily requiring theirperformance in the particular order discussed or illustrated, unlessspecifically identified as an order of performance. It is also to beunderstood that additional or alternative steps may be employed.

References to “an electronic computer” and “a processor” or “themicroprocessor” and “the processor,” can be understood to include one ormore of these devices that can communicate in a stand-alone and/or adistributed environment(s), and can thus be configured to communicatevia wired or wireless communications with other processors, where suchone or more processor can be configured to operate on one or moreprocessor-controlled devices that can be similar or different devices.Furthermore, references to memory, unless otherwise specified, caninclude one or more processor-readable and accessible memory elementsand/or components that can be internal to the processor-controlleddevice, external to the processor-controlled device, and can be accessedvia a wired or wireless network.

References to “a processor” should be understood to include electroniccomputers, microprocessors, microcontrollers, FPGA devices, ASIC devicesand similar programmable or program defined electronic circuits andcollections of such devices that can communicate in a stand-alone and/ora distributed environment(s), and can thus be configured to communicatevia wired or wireless communications with other processors. Furthermore,references to memory, unless otherwise specified, can include one ormore processor-readable and accessible memory elements and/or componentsthat can be internal to the processor or external to the processor andaccessed via a wired or wireless network.

It is specifically intended that the present invention not be limited tothe embodiments and illustrations contained herein and the claims shouldbe understood to include modified forms of those embodiments includingportions of the embodiments and combinations of elements of differentembodiments as come within the scope of the following claims. All of thepublications described herein, including patents and non-patentpublications, are hereby incorporated herein by reference in theirentireties.

What we claim is:
 1. An electrical stimulation device for improvingwaste clearance through a perivascular system comprising: an intraoraldevice receivable within a human mouth; at least one electrode supportedby the intraoral device configured to stimulate a facial nerve; anelectrical generator generating a carrier wave delivered to the at leastone electrode having a carrier frequency, the electrical generatorstimulating the perivascular system into increased CSF and ISF flow; andat least one sensor supported by the intraoral device configured todetect biomarkers indicating an increased cerebral spinal fluid (CSF)and interstitial fluid (ISF) flow.
 2. The electrical stimulation deviceof claim 1 wherein the biomarkers are analytes of tissue or saliva. 3.The electrical stimulation device of claim 2 wherein the analytes are atleast one of amyloid beta peptide, tau protein, lactoferrin,alpha-synuclein, DJ-1 protein, chromogranin A, huntingtin protein, DNAmethylation disruptions, and micro-RNA profiles.
 4. The electricalstimulation device of claim 2 wherein the at least one sensor isconfigured to detect increased levels of neuronal cytokines.
 5. Theelectrical stimulation device of claim 1 wherein the biomarkers are atleast one of a brain wave frequency and heart rate further indicating anincreased cerebral spinal fluid (CSF) and interstitial fluid (ISF) flow.6. The electrical stimulation device of claim 5 wherein the at least oneelectrode is configured to detect changes in low brain wave frequency 7.The electrical stimulation device of claim 1 wherein the at least oneelectrode is adapted to stimulate at least one of a trigeminal nerve,buccal branch nerve, mental branch nerve and facial branch nerve.
 8. Theelectrical stimulation device of claim 1 wherein the intraoral device isa mouthpiece configured to engage a jaw of a user's mouth.
 9. Theelectrical stimulation device of claim 1 wherein the intraoral device isa dental filling configured to be inserted within a cavity of a tooth.10. The electrical stimulation device of claim 1 further comprising anelectrical modulation generator configured to generate a modulation wavehaving a predetermined periodicity providing a first period ofstimulation of the perivascular system and a second period of relaxationof the perivascular system, the predetermined periodicity selected toincrease pulsatility over continuous stimulation of the perivascularsystem by the carrier frequency; and a modulator receiving the carrierwave and the modulation wave and modulating the carrier wave forapplication to the at least one electrode.
 11. A method of improvingwaste clearance through a perivascular system comprising: positioning atleast one electrode supported by an intraoral device in close proximityto a facial nerve; generating a carrier wave having a carrier frequencystimulating the perivascular system into increased cerebral spinal fluid(CSF) and interstitial fluid (ISF) flow; applying the carrier wave tothe at least one electrode; and detecting biomarkers indicating anincreased cerebral spinal fluid (CSF) and interstitial fluid (ISF) flow.12. The method of claim 11 wherein the biomarkers are analytes of tissueor saliva.
 13. The method of claim 12 wherein the analytes are at leastone of amyloid beta peptide, tau protein, lactoferrin, alpha-synuclein,DJ-1 protein, chromogranin A, huntingtin protein, DNA methylationdisruptions, and micro-RNA profiles.
 14. The method of claim 12 whereinthe at least one sensor is configured to detect increased levels ofneuronal cytokines.
 15. The method of claim 11 wherein the biomarkersare at least one of a brain wave frequency and heart rate furtherindicating an increased cerebral spinal fluid (CSF) and interstitialfluid (ISF) flow.
 16. The method of claim 15 wherein the at least oneelectrode is configured to detect changes in low brain wave frequency.17. The method of claim 11 wherein the facial nerve is at least one of atrigeminal nerve, buccal branch nerve, mental branch nerve and facialbranch nerve.
 18. The method of claim 11 further comprising generating amodulation wave having a predetermined periodicity providing a firstperiod of stimulation of the perivascular system and a second period ofrelaxation of the perivascular system, the predetermined periodicityselected to increase waste clearance over continuous stimulation of theperivascular system by the carrier frequency; and modulating the carrierwave.